Colony-stimulating factor 1 (CSF-1) stimulates the proliferation and supports the differentiation and survival of cells of the mononuclear phagocyte lineage. Its pleiotropic actions are mediated through its binding to a single class of CSF-1 receptors (CSF-1R) encoded by the c- fms proto-oncogene. The ligand-activated CSF-1R tyrosine kinase phosphorylates cytoplasmic effector molecules, which act in concert to relay signals that govern the transcription of CSF-1 responsive genes. Although signals triggered by the CSF-1 receptor induce a series of canonical "immediate early response" genes (e.g. c-fos, junB, c-jun, c- myc, etc.) within 1-2 hours following growth factor stimulation, the continued requirement for CSF-1 throughout the entire G1 interval suggests that the activation of other "delayed early response" genes is also required to ensure progression into S-phase. The latter genes include a novel family of D-type G1 cyclins that are hypothesized to integrate growth factor-induced signals with the cell cycle clock, thereby regulating temporal transitions through one or more G1 control points. Recent evidence suggests that deregulated expression of D-type cyclin genes can contribute to neoplasia. At least two distinct D-type cyclin genes are targets of chromosomal translocations, gene amplification, and retroviral insertional mutagenesis in a variety of tumors, including B and T cell lymphomas, parathyroid adenomas, and possibly, carcinomas of the breast, head, and neck. We have cloned the human cyclin D1, D2, and D3 genes, mapped them to chromosomes 11q13, 12p13, and 6p21, respectively, and have begun to screen tumor material and cell lines established from patients with different hematopoietic malignancies for chromosomal rearrangements that might affect cyclin D transcription. Because cyclins normally function as regulatory subunits of cyclin- dependent kinases (cdks), we are attempting to identify the cdk partner(s) of D-type cyclins and, ultimately, hope to extend the genetic analyses to these as yet unidentified loci. We are also exploring the possibility that the effects of cyclin D/cdk may be mediated through their interaction with the retinoblastoma gene product (p105Rb) and/or related proteins (the Rb-like p107 protein), which have in turn been implicated in negatively regulating cell cycle progression. The theme of this project conforms with the overall goals of this Program Project Grant, but because the work has been funded through an independent mechanism, no direct support is requested.